Our purpose was to assess the effect of computer-aided detection (CAD) on lesion detection as a second reader in computed tomographic colonography, and to compare the influence of CAD on the performance of readers with different levels of expertise. Fifty-two CT colonography patient data-sets (37 patients: 55 endoscopically confirmed polyps > or =0.5 cm, seven cancers; 15 patients: no abnormalities) were retrospectively reviewed by four radiologists (two expert, two nonexpert). After primary data evaluation, a second reading augmented with findings of CAD (polyp-enhanced view, Siemens) was performed. Sensitivities and reading time were calculated for each reader without CAD and supported by CAD findings. The sensitivity of expert readers was 91% each, and of nonexpert readers, 76% and 75%, respectively, for polyp detection. CAD increased the sensitivity of expert readers to 96% (P = 0.25) and 93% (P = 1), and that of nonexpert readers to 91% (P = 0.008) and 95% (P = 0.001), respectively. All four readers diagnosed 100% of cancers, but CAD alone only 43%. CAD increased reading time by 2.1 min (mean). CAD as a second reader significantly improves sensitivity for polyp detection in a high disease prevalence population for nonexpert readers. CAD causes a modest increase in reading time. CAD is of limited value in the detection of cancer.